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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2863—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present invention relates to combination therapies useful for treating cancer.
• the present invention relates to therapeutically effective combinations of a pan ErbB family inhibitor and a KRas G12C inhibitor, pharmaceutical compositions comprising the inhibitors, kits comprising the compositions and methods of use therefor.
• KRas Kirsten Rat Sarcoma 2 Viral Oncogene Homolog
• GDP-bound inactive
• GTP-bound active
• cellular proliferation e.g., see Alamgeer et ah, (2013) Current Opin Pharmcol. 13:394-401.
• Single nucleotide substitutions that result in missense mutations at codons 12 and 13 of the KRas primary amino acid sequence comprise approximately 40% of these KRas driver mutations in lung adenocarcinoma, with a G12C transversion being the most common activating mutation (e.g., see Dogan et ah, (2012) Clin Cancer Res. 18(22):6169-6177, published online 2012 Sep 26. doi: 10.1 158/1078-0432.CCR- 1 1-3265).
• KRas inhibitor has demonstrated sufficient safety and/or efficacy to obtain regulatory approval (e.g., see
• KRas G12C inhibitors disclosed herein are potent inhibitors of KRas G12C enzymatic activity and exhibit single agent activity inhibiting the in vitro proliferation of cell lines harboring a KRas G12C mutation
• the relative potency and or observed maximal effect of any given KRas G12C inhibitor can vary between KRAS mutant cell lines.
• the reason or reasons for the range of potencies and observed maximal effect is not fully understood but certain cell lines appear to possess differing intrinsic resistance.
• the combination therapy of the present invention in one aspect, synergistically increases the potency of KRas G12C inhibitors resulting in improved efficacy of KRas G12C inhibitors disclosed herein.
• the combination therapy of the present invention in another aspect, provides improved clinical benefit to patients compared to treatment with KRas G12C inhibitors disclosed herein as a single agent.
• kits for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of a pan ErbB family inhibitor and a KRAS G12C inhibitor of formula (I):
• X is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted with one or more R 8 ;
• Y is a bond, O, S or NR 5 ;
• R 2 is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl,
• Z is C l - C4 alkylene
• each R 3 is independently C l - C3 alkyl, oxo, or haloalkyl;
• L is a bond, -C(O)-, or Cl - C3 alkylene;
• R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionally substituted with one or more R 6 or R 7 ;
• each R 3 is independently hydrogen or Cl - C3 alkyl
• R 6 is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with one or more R 7 ;
• each R 7 is independently halogen, hydroxyl, Cl - C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxy alkyl or Q-haloalkyl, wherein Q is O or S;
• R 8 is oxo, Cl - C3 alkyl, C2 - C4 alkynyl, heteroalkyl, cyano, -C(0)OR 5 , -C(0)N(R 3 ) 2 , - N(R 5 ) 2 , wherein the Cl - C3 alkyl may be optionally substituted with cyano, halogen, -OR 5 , - N(R 5 ) 2 , or heteroaryl
• each R 9 is independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen,
• Cl - C6 alkyl aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein the Cl - C6 alkyl may be optionally substituted with cycloalkyl;
• each R 10 is independently hydrogen, acyl, Cl - C3 alkyl, heteroalkyl or hydroxyalkyl;
• R 1 1 is haloalkyl
• R A is absent, hydrogen, deuterium, cyano, halogen, Cl - C-3 alkyl, haloalkyl, heteroalkyl, -C(0)N(R 5 ) 2 , or hydroxyalkyl;
• each R B is independently hydrogen, deuterium, cyano, Cl - C3 alkyl, hydroxyalkyl, heteroalkyl, Cl C3 alkoxy, halogen, haloalkyl, -ZNR 3 R n , -C(0)N(R 5 ) 2 , -NHC(0)C1 - C3 alkyl, -CH 2 NHC(0)C1 - C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and Cl - C3 alkyl, wherein the heteroaryl or the heteroaryl portion of the heteroarylalkyl is optionally substituted with one or more R 7 ; [0027] m is zero or an integer between 1 and 2;
• p is one or two; and wherein,
• R a , R B and the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl optionally substituted with one or more R 7 .
• KRas G12C inhibitor [0031] Also included for use in the methods provided herein are KRas G12C inhibitor
• R 1 , R 3 , R 4 , R 3 , R 10 , R 1 1 , L and m are as defined for Formula I, and the piperazinyl ring is optionally substituted with R 8 wherein R 8 is as defined for Formula I.
• KRas G12C inhibitor [0033] Also included for use in the methods provided herein are KRas G12C inhibitor
• R 1 , R 3 , R 4 , L and m are as defined for Formula I
• R 2 is heterocyclylalkyl optionally substituted with one or more R 9 where R 9 is as defined for Formula I
• the piperazinyl ring is optionally substituted with R 8 , where R 8 is as defined for Formula I.
• compositions for use in the methods comprising a therapeutically effective amount of a combination of a pan ErbB family inhibitor and a KRas G12C inhibitor compound Formula I, Formula I-A, or Formula 1- B, or a pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient.
• kits for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of a pan ErbB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and a KRAS G12C inhibitor of Formula (I), Formula I-A or Formula I-B, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
• the cancer is a KRas G12C-associated cancer.
• the KRas G12C-associated cancer is lung cancer.
• KRas G12C inhibitor compounds and pan ErbB family inhibitors are the only active agents in the provided compositions and methods.
• the pan ErbB family inhibitor is an irreversible inhibitor.
• irreversible pan ErbB family inhibitors suitable for the provided compositions and methods include, but are not limited to, Afatinib; Dacomitinib; Canertinib; Poziotinib, AV 412; PF 6274484 and HKI 357.
• the pan ErbB family inhibitor is a reversible inhibitor.
• reversible pan ErbB family inhibitors suitable for the provided compositions and methods include, but are not limited to erlotinib, gefitinib, sapitinib; varlitinib; TAK-285 (N-[2-[4-[3- chloro-4-[3-(trifluoiOmethyl)phenoxy]phenylamino]-5H-pyrrolo[3,2-d]pyriniidin-5-yl]ethyl]-3- hydroxy-3-methylbutyramide); AEE788 (6-[4-(4-Ethylpiperazin- 1 -ylmethyl)phenyl]-N-[l (R)- phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine);tarloxotinib 3-[N-[4-(3-Bromo-4- chlorophenylamino)pyrid
• the pan ErbB family inhibitor is a combination of an EGFR inhibitor and a HER2 inhibitor, wherein the EGFR inhibitor and the FIER2 inhibitor are a combination of two of: AG 1478 (N-(3-chlorophenyl)-6-methoxy-7-[l lC]methoxyquinazolin-4-amine); AG 555 (2-cyano-3-(3,4-dihydiOxyphenyl)-N-(3-phenylpropyl)-2(E)-propenamide); AG 556 ((E)-2- cyano-3-(3,4-dihydroxyphenyl)-N-(4-phenylbutyl)acrylamide; AG 825 (3-[3-(benzothiazol-2- ylsulfanylmethyl)-4-hydroxy-5-methoxyphenyl]-2-cyano-2-propenamide); CP 724714 (2- methoxy-N-[3-[4-[3-methyl
• the pan ErbB family inhibitor is an anti-EGFR antibody, a anti- FIER2 antibody or combination of an anti-EGFR antibody and anti-HER2 antibody.
• Antibodies including monoclonal antibodies, antibody conjugates and bispecific antibodies, targeting EGFR and/or HER2 are well known and a number of antibodies are commercially available for research and human clinical use.
• anti-EGFR antibodies suitable for the provided compositions and methods include necitumumab, panitumumab and cetuximab.
• anti-HER2 antibodies suitable for the provided compositions and methods include, pertuzumab, trastuzumab, and trastuzumab emtansine.
• the invention provides for methods for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor, comprising contacting the cancer cell with a
• the contacting is in vitro. In one embodiment, the contacting is in vivo.
• a KRas G12C mutation e.g., a KRas Gl2C-associated cancer
• a regulatory agency-approved
• kits comprising a pan ErbB inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula I-A or Formula I-B, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
• a kit comprising a pan ErbB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula I-A or Formula I-B, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, for use in treating a KRas G12C cancer.
• the invention provides a kit containing a dose of a pan ErbB inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula I-A or Formula I-B, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof in an amount effective to inhibit proliferation of cancer cells in a subject.
• the kit in some cases includes an insert with instructions for administration of the a pan ErbB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula I-A or Formula I-B, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
• the insert may provide a user with one set of instructions for using the a pan ErbB family inhibitor, or a pharmaceutically acceptable salt or a
• the patient before treatment with the compositions or methods of the invention, was treated with one or more of a chemotherapy, a targeted anticancer agent, radiation therapy, and surgery, and optionally, the prior treatment was unsuccessful; and/or the patient has been administered surgery and optionally, the surgery was unsuccessful; and/or the patient has been treated with a platinum- based chemotherapeutic agent, and optionally, the patient has been previously determined to be non-responsive to treatment with the platinum-based chemotherapeutic agent; and/or the patient has been treated with a kinase inhibitor, and optionally, the prior treatment with the kinase inhibitor was unsuccessful; and/or the patient was treated with one or more other therapeutic agent(s).
• the present invention relates to combination therapies for treating KRas G12C cancers.
• the present invention relates to methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a pan ErbB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and a KRAS G12C inhibitor of Formula (I), Formula I-A or Formula I-B, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, pharmaceutical compositions each separately comprising a therapeutically effective amount of the inhibitors, kits comprising the compositions and methods of use therefor.
• Combinations of a pan ErbB family inhibitor with a KRas G12C inhibitor compounds of Formula (I), Formula I-A or Formula I-B, or a pharmaceutically acceptable salt thereof synergistically increase the potency of the KRas G12C inhibitor compounds of Formula (I), Formula I-A or Formula I-B, or a pharmaceutically acceptable salt thereof against cancer cells that express KRas G12C thereby increasing the efficacy and therapeutic index of KRas G12C inhibitor compounds of Formula (I), Formula I-A or Formula I-B , and pharmaceutically acceptable salts thereof.
• KRas G12C refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a cysteine for a glycine at amino acid position 12.
• the assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variant p.Glyl2Cys.
• a“KRas G12C inhibitor” refers to compounds of the present invention that are represented by Formula (I), Formula I-A and Formula I-B, and pharmaceutically acceptable salts thereof as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12C.
• the KRas G12C inhibitors of the present invention interact with and irreversibly bind to KRas G12C by forming a covalent adduct with the sulfhydryl side chain of the cysteine residue at position 12 resulting in the inhibition of the enzymatic activity of KRas G12C.
• the KRas G12C inhibitor is a compound selected from compound Nos 1 -678 (as numbered in WO2019099524), or pharmaceutically acceptable salts thereof (e.g., Example Nos 234, 359,
• KRas Gl2C-associated disease or disorder refers to diseases or disorders associated with or mediated by or having a KRas G12C mutation.
• a non-limiting example of a KRas G12C-associated disease or disorder is a KRas G12C-associated cancer.
• an“ErbB family” or“ErbB family member” refers to a member of a mammalian transmembrane protein tyrosine kinase family including: EGFR, ErbB2 (HER2), ErbB 3 (HER3), and ErbB4 (HER4).
• a“pan ErbB family inhibitor” refers to an agent, e.g., a compound or antibody, that is capable of negatively modulating or inhibiting all or a portion of the activity of at least one member of the ErbB family.
• the modulation or inhibition of one or more ErbB family members may occur through modulating or inhibiting kinase enzymatic activity of one or more ErbB family member or by blocking homodimerization or heterodimerization of ErbB family members.
• the term“pan ErbB inhibitor” refers to the use of a single pan ErbB inhibitor.
• the term“pan ErbB inhibitor” refers to the use of two pan ErbB inhibitors.
• the term“subject,” “individual,” or “patient,” used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans.
• the patient is a human.
• the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.
• the subject has been identified or diagnosed as having a cancer having a KRas G12C mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
• the subject has a tumor that is positive for a KRas G12C mutation (e.g., as determined using a regulatory agency-approved assay or kit).
• the subject can be a subject with a tumor(s) that is positive for a KRas G12C mutation (e.g., identified as positive using a regulatory agency- approved, e.g., FDA-approved, assay or kit).
• the subject can be a subject whose tumors have a KRas G12C mutation (e.g., where the tumor is identified as such using a regulatory agency- approved, e.g., FDA-approved, kit or assay).
• the subject is suspected of having a KRas G12C gene-associated cancer ln some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a KRas G12C mutation (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).
• the term“pediatric patient” as used herein refers to a patient under the age of 16 years at the time of diagnosis or treatment.
• the term“pediatric” can be further be divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)).
• Berhman RE Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.
• an assay is used to determine whether the patient has KRas G12C mutation using a sample (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a KRas G12C-associated cancer, a patient having one or more symptoms of a KRas G12C-associated cancer, and/or a patient that has an increased risk of developing a KRas G12C-associated cancer) can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR, quantitative real-time RT-PCR, allele-specific genotyping or ddPCR).
• the assays are typically performed
• regulatory agency is a country’s agency for the approval of the medical use of pharmaceutical agents with the country.
• a regulatory agency is the U.S. Food and Drug Administration (FDA).
• amino refers to -NH 2 ;
• alkyl refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms, 1 -8 carbon atoms 1-6 carbon atoms, or 1-3 carbon atoms which is optionally substituted with one, two or three substituents. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
• haloalkyl refers to an alkyl chain in which one or more hydrogen has been replaced by a halogen.
• haloalkyls are trifluoromethyl, difluoromethyl and fluoromethyl.
• haloalkyloxy refers to -O-haloalkyl
• alkylene group is an alkyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.
• alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene.
• alkoxy refers to -OC1 - C6 alkyl.
• cycloalkyl as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, for example 3 to 8 carbons, and as a further example 3 to 6 carbons, wherein the cycloalkyl group additionally is optionally substituted.
• cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
• heteroalkyl refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are replaced by a heteroatom selected from the group consisting of O, S, and N.
• hydroxyalkyl refers to -alkyl-OH.
• dihydroxyalkyl refers to an alkyl group as defined herein wherein two carbon atoms are each substituted with a hydroxyl group.
• alkylaminyl refers to -NR x -alkyl, wherein R x is hydrogen. In one embodiment, R x is hydrogen.
• dialkylaminyl refers to -N(R y ) 2 , wherein each R y is Cl - C3 alkyl.
• alkylaminylalkyl refers to -alkyl-NR x -alkyl, wherein R x is hydrogen. In one embodiment, R x is hydrogen.
• dialkylaminylalkyl refers to -alkyl-N(R y ) 2 , wherein each R y is Cl - C4 alkyl, wherein the alkyl of the— alkyl-N(R y ) 2 may be optionally substituted with hydroxy or hydroxy alkyl.
• aryl group is a C 6 -Ci4 aromatic moiety comprising one to three aromatic rings, which is optionally substituted.
• the aryl group is a C 6 -Cio aryl group.
• aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl.
• an "aralkyl” or “arylalkyl” group comprises an aryl group covalently linked to an alkyl group, either of which may independently be optionally substituted or unsubstituted.
• An example of an aralkyl group is (Ci- C 6 )alkyl(C 6 -Cio)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.
• An example of a substituted aralkyl is wherein the alkyl group is substituted with hydroxyalkyl.
• a “heterocyclyl” or “heterocyclic” group is a ring structure having from about 3 to about 12 atoms, for example 4 to 8 atoms, wherein one or more atoms are selected from the group consisting of N, O, and S, the remainder of the ring atoms being carbon.
• the heterocyclyl may be a monocyclic, a bicyclic, a spirocyclic or a bridged ring system.
• the heterocyclic group is optionally substituted with R 7 on carbon or nitrogen at one or more positions, wherein R 7 is as defined for Formula I.
• the heterocyclic group is also independently optionally substituted on nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or on sulfur with oxo or lower alkyl.
• heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl,
• thiomorpholinyl thiomorpholinyl 1 ,1 dioxide
• morpholinyl oxazepanyl
• azabicyclohexanes azabicycloheptanes and oxa azabiocycloheptanes.
• heterocyclylalkyl refers to a heterocyclyl group as defined herein linked to the remaining portion of the molecule via an alkyl linker, wherein the alkyl linker of the heterocyclylalkyl may be optionally substituted with hydroxy or hydroxyalkyl.
• heteroaryl refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 p electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S.
• heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
• tetrahydroisoquinolinyl tetrahydroquinolinyl, tetrazolyl, 6H-l ,2,5-thiadiazinyl, 1,2,3- thiadiazolyl, 1 ,2,4-thiadiazolyl, l,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, l,2,3-triazolyl, 1,2,4-triazolyl, l,2,5-triazolyl, l,3,4-triazolyl, and xanthenyl.
• a "heteroarylalkyl” group comprises a heteroaryl group covalently linked to an alkyl group, wherein the radical is on the alkyl group, either of which is independently optionally substituted or unsubstituted.
• heteroarylalkyl groups include a heteroaryl group having 5, 6, 9, or 10 ring atoms bonded to a C1-C6 alkyl group.
• heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl isoquinolinylmethyl, isoinodylmethyl, cinnolinylmethyl, and benzothiophenylethyl. Specifically excluded from the scope of this term are compounds having adjacent annular O and/or S atoms.
• an effective amount of a compound is an amount that is sufficient to negatively modulate or inhibit the activity of the desired target, i.e., ErbB family member or KRas G12C. Such amount may be administered, for example, as a single dosage or may be administered according to a regimen, whereby it is effective.
• a "therapeutically effective amount" of a compound is an amount that is sufficient to ameliorate, or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of ErbB family member(s) or KRas G12C. Such amount may be administered, for example, as a single dosage or may be administered according to a regimen, whereby it is effective.
• a "therapeutically effective amount of a combination" of two compounds is an amount that together synergistically increases the activity of the combination in comparison to the therapeutically effective amount of each compound in the combination, i.e., more than merely additive effect.
• a KRas G12C inhibitor compound of Formula (I), Formula I-A, or Formula I-B, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof results in an increased duration of overall survival (“OS”) in subjects relative to treatment with only the KRas G12C inhibitor.
• OS overall survival
• the therapeutically effective amount of the combination of a pan ErbB inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula I-A, or Formula I-B, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof results in increased tumor regression in subjects relative to treatment with only the KRas G12C inhibitor.
• the therapeutically effective amount of the combination of a pan ErbB inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula I-A, or Formula I-B, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof results in increased tumor growth inhibition in subjects relative to treatment with only the KRas G12C inhibitor.
• the therapeutically effective amount of the combination of a pan ErbB inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula I-A, or Formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof results in an improvement in the duration of stable disease in subjects compared to treatment with only the KRas G12C inhibitor.
• Such amounts may be administered, for example, as a single dosage or may be administered according to a regimen, whereby it is effective.
• treatment means any manner in which the symptoms or pathology of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.
• amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.
• the term“about” when used to modify a numerically defined parameter means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg/kg may vary between 4.5 mg/kg and 5.5 mg/kg. “About” when used at the beginning of a listing of parameters is meant to modify each parameter. For example, about 0.5 mg, 0.75 mg or 1.0 mg means about 0.5 mg, about 0.75 mg or about 1.0 mg. Likewise, about 5% or more, 10% or more, 15% or more, 20% or more, and 25% or more means about 5% or more, about 10% or more, about 15% or more, about 20% or more, and about 25% or more.
• a KRas G12C-associated cancer for example a KRas G12C-associated cancer, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a pan ErbB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and a KRAS G12C inhibitor of Formula (I), Formula I-A or Formula I-B, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
• Epidermal Growth Factor Receptor is a transmembrane protein tyrosine kinase of the ErbB receptor family.
• the EGFR receptor can homo-dimerize with another EGFR molecule or hetero-dimerize with another family member such as ErbB2 (HER2), ErbB3 (HER3), or ErbB4 (FIER4).
• HER2 ErbB2
• HER3 ErbB3
• FIER4 ErbB4
• Flomo- and/or hetero- dimerization of ErbB receptors results in the phosphorylation of key tyrosine residues in the intracellular domain and leads to the stimulation of numerous intracellular signal transduction pathways involved in cell proliferation and survival.
• EGFR activating mutations have been detected in a subset of non small cell lung cancers (NSCLCs) tumors. These mutations tend to occur within EGFR exons 18-21 , which encodes a portion of the EGFR kinase domain. Approximately 90% of these mutations are exon 19 deletions or exon 21 L858R point mutations (Ladanyi and Pao (2008)
• the pan ErbB family inhibitors used in the methods of the present invention may be reversible or irreversible ErbB family inhibitors.
• the pan ErbB family inhibitor inhibits the activity of more than one ErbB family member.
• the pan ErbB family inhibitor is an irreversible inhibitor.
• Irreversible pan ErbB family inhibitors inhibit the activity of EGFR and HER2 by forming a covalent bond with the sulfhydryl group of cysteine 797 and cysteine 773, respectively, that blocks the binding of ATP to the intracellular catalytic domain.
• these inhibitors are active against, for example, cell lines harboring EGFR exon 19 deletions/insertions, and L858R and T790M resistant mutations.
• Exemplary irreversible pan ErbB family inhibitors for use in the methods include afatinib ((E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-4- (dimethylamino)but-2-enamide); dacomitinib ((2£ ' )-iV- ⁇ 4-[(3-Chloro-4-fluorophenyl)amino]-7- methoxy-6-quinazolinyl ⁇ -4-(l-piperidinyl)-2-butenamide); canertinib (N-(4-((3-chloro-4- fluorophenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl)acrylamide); poziotinib (l-(4-((4- ((3,4-d
• the pan ErbB family inhibitor is a reversible inhibitor.
• Exemplary reversible pan EGFR family inhibitors include erlotinib ([6,7-Bis-(2-methoxy-ethoxy)- quinazolin-4-yl]-(3-ethynyl-phenyl)-amine)), gefitinib (4-(3'-chloro-4'-fluoroanilino)-7-methoxy- 6-(3-morpholinopropoxy)quinazoline, sapitinib (2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7- methoxyquinazolin-6-yl)oxy)piperidin- 1 -yl)-N-methy lacetamide); varlitinib ((R)-N4-(3-chloro- 4-(thiazol-2-ylmethoxy)phenyl)-N6-(4-methyl
• the pan ErbB family inhibitor is a combination of an EGFR inhibitor and a FIER2 inhibitor, wherein the EGFR inhibitor and the HER2 inhibitor are a combination of two of: AG 1478 FIC1 (7V-(3-Chlorophenyl)-6,7-dimethoxy-4-quinazolinanine hydrochloride);
• PD 153035 (4-[(3-Bromophenyl)amino]-6,7-dimethoxyquinazoline
• PD 158780 (A 4 -(3-Bromophenyl)-A ⁇ -methyl-pyrido[3,4-i7]pyrimidine-4,6- diamine), and pharmaceutically acceptable salts or a pharmaceutical compositions thereof.
• pan ErbB family inhibitors that target wild type and mutant ErbB family members are well known to those skilled in the art and pan ErbB family inhibitors may be obtained from a wide-variety of commercial suppliers, in forms suitable for both research or human use.
• suitable reversible and irreversible pan ErbB family inhibitors for use in the compositions and methods disclosed herein, and methods for preparing such inhibitors are disclosed in US Patent Application Publication Nos: US20180050993; US20180016268; US20180008607; US20170362204; US 20170362203; US20170355683; US20170342055; US20170267671 ; US20170183330; US20170174697; 20170008856; US20160375148; US20160332994; US20160257682; US 20160244469; US 20160337610; US20160102076; US20160016948; US20150284340; US20150274678;
• the pan ErbB family inhibitor is an anti-EGFR antibody, an anti- HER2 antibody or a combination of an anti-EGFR antibody and anti-UER2 antibody, or pharmaceutical compositions thereof.
• Antibodies including monoclonal antibodies, antibody drug conjugates and bispecific antibodies, targeting EGFR and/or HER-2 are well known and a number of antibodies are commercially available for research and human clinical use.
• Exemplary anti-EGFR monoclonal antibodies approved for human clinical use include, but are not limited to, necitumumab (Eli Lilly), panitumumab (Amgen) and cetuximab
• the anti-EGFR monoclonal antibody is cetuximab.
• anti-HER-2 monoclonal antibodies approved for human clinical use include, but are not limited to, pertuzumab (Roche), trastuzumab (Roche) and trastuzumab emtansine (Roche).
• Other anti-fler2 antibodies, antibody drug conjugates and bispecific antibodies suitable for use in the methods include those disclosed in United States Patent Application Publication Nos: US 20030228663; US 20060018899; US 20090187007; US 20090285837; US
• the KRas G12C inhibitors used in the methods are compounds of Formula (I):
• X is a 4- 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted with one or more R 8 ;
• Y is a bond, O, S or NR 5 ;
• R 2 is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl,
• heteroarylalkyl wherein each of the Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl may be optionally substituted with one or more R 9 ;
• Z is C l - C4 alkylene
• each R 3 is independently C l - C3 alkyl, oxo, or haloalkyl;
• L is a bond, -C(O)-, or C l - C3 alkylene;
• R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionally substituted with one or more R 6 or R 7 ;
• each R 5 is independently hydrogen or Cl - C3 alkyl
• R 6 is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with one or more R 7 ;
• each R 7 is independently halogen, hydroxyl, Cl - C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;
• R 8 is oxo, Cl - C3 alkyl, C2 - C4 alkynyl, heteroalkyl, cyano, -C(0)OR 5 , -C(0)N(R 3 ) 2 , - N(R 5 ) 2 , wherein the Cl - C3 alkyl may be optionally substituted with cyano, halogen, -OR 5 , - N(R3 ⁇ 4 or heteroaryl;
• each R 9 is independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen,
• dialkylaminyl dialkylamidoalkyl, or dialkylaminylalkyl, wherein the Cl - C6 alkyl may be optionally substituted with cycloalkyl;
• each R 10 is independently hydrogen, acyl, Cl - C3 alkyl, heteroalkyl or hydroxyalkyl; [0119] R" is haloalkyl;
• R A is absent, hydrogen, deuterium, cyano, halogen, Cl - C-3 alkyl, haloalkyl, heteroalkyl, -C(0)N(R 5 ) 2 , or hydroxyalkyl;
• each R B is independently hydrogen, deuterium, cyano, Cl - C3 alkyl, hydroxyalkyl, heteroalkyl, Cl - C3 alkoxy, halogen, haloalkyl, -ZNR 5 R n , -C(0)N(R : ’) 2 , -NHC(0)C1 - C3 alkyl, -CH 2 NHC(0)C1 - C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or
• heterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and Cl - C3 alkyl, wherein the heteroaryl or the heteroaryl portion of the heteroarylalkyl is optionally substituted with one or more R 7 ; [0122] m is zero or an integer between 1 and 2;
• p is one or two; and wherein,
• R A is present
• R B is present and p equals two, or R a , R B and the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl optionally substituted with one or more R 7 .
• KRas G12C inhibitors used in the methods herein include compounds having the Formula I- A:
• R 1 , R 3 , R 4 , R 5 , R 10 , L and m are as defined for Formula I, R 1 1 is hydrogen, methyl or hydroxyalkyl, and the piperidinyl ring is optionally substituted with R 8 wherein R 8 is as defined for Formula I.
• KRas G12C inhibitors used in the methods herein include compounds having the Formula I-B:
• KRas G12C inhibitor compounds of Formula (I), Formula I-A and Formula I-B useful in the methods disclosed herein are selected from the group consisting of Example Nos 1-678 including the following structures:
• the KRas G12C inhibitor is selected from:
• the KRas G12C inhibitor is:
• the KRas G12C inhibitor is:
• the KRas G12C inhibitor is:
• the KRas G12C inhibitor is:
• Example 507 (also referred to as Example 507) or a pharmaceutically acceptable salt thereof.
• the KRas G12C inhibitors used in the methods of the present invention may have one or more chiral center and may be synthesized as stereoisomeric mixtures, isomers of identical constitution that differ in the arrangement of their atoms in space.
• the compounds may be used as mixtures or the individual components/isomers may be separated using commercially available reagents and conventional methods for isolation of stereoisomers and enantiomers well-known to those skilled in the art, e.g., using CHIRALPAK® (Sigma-Aldrich) or
• CHIRALCET ⁇ (Diacel Corp) chiral chromatographic HPLC columns according to the manufacturer’s instructions.
• compounds of the present invention may be synthesized using optically pure, chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Unless otherwise indicated, whenever the specification, including the claims, refers to compounds of the invention, the term“compound” is to be understood to encompass all chiral (enantiomeric and diastereomeric) and racemic forms.
• the KRas G12C inhibitor compounds of Formula I, Formula I-A, or Formula I-B used in the methods include trifluoroacetic acid salts of the above compounds.
• Pan ErbB inhibitors and the KRas G12C compounds of Formula (I), Formula I-A, or Formula I-B or pharmaceutically acceptable salts thereof may be formulated into
• the invention provides pharmaceutical compositions comprising a pan ErbB family inhibitor and KRas G12C inhibitor according to the invention and a
• pan ErbB family inhibitor and KRas G12C inhibitor may be any pharmaceutically acceptable carrier, excipient, or diluent that may be used in the methods disclosed herein.
• the pan ErbB family inhibitor and KRas G12C inhibitor may be any pharmaceutically acceptable carrier, excipient, or diluent that may be used in the methods disclosed herein.
• the pan ErbB family inhibitor and KRas G12C inhibitor may be any pharmaceutically acceptable carrier, excipient, or diluent that may be used in the methods disclosed herein.
• pan ErbB family inhibitor and KRas G12C inhibitor are administered intravenously in a hospital setting. In one embodiment, administration may be by the oral route.
• compositions may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
• diluents fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
• the preparation of pharmaceutically acceptable formulations is described in, e.g., Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.
• the term pharmaceutically acceptable salt refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects.
• examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid.
• inorganic acids for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like
• organic acids such as acetic acid, oxalic acid, tartaric acid
• the compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula— NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
• R is hydrogen, alkyl, or benzyl
• Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulf
• the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated.
• a dose of the active compound for all o f the above-mentioned conditions is in the range from about 0.01 to 300 mg/kg, for example 0.1 to 100 mg/kg per day, and as a further example 0.5 to about 25 mg per kilogram body weight of the recipient per day.
• a typical topical dosage will range from 0.01 -3% wt/wt in a suitable carrier.
• the effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.
• compositions comprising a pan ErbB family inhibitor and a KRas G12C inhibitor may be used in the methods of use described herein.
• pan ErbB family inhibitor and the KRas G12C inhibitor can be formulated into separate or individual dosage forms which can be co-administered one after the other. Another option is that if the route of administration is the same (e.g. oral) two active compounds can be formulated into a single form for co-administration, both methods of co-administration, however, being part of the same therapeutic treatment or regimen.
• compositions comprising a pan ErbB family inhibitor and/or a KRas G12C inhibitor for use in the methods may be for simultaneous, separate or sequential use.
• the pan ErbB family inhibitor is administered prior to administration of the KRas G12C inhibitor compound of Formula (I), Formula I-A or Formula I-B.
• the pan ErbB family inhibitor is administered after administration of the KRas G12C inhibitor compound of Formula (I), Formula I-A or Formula I-B.
• the pan ErbB family inhibitor is administered at about the same time as administration of the KRas G12C inhibitor compound of Formula (I), Formula I-A or Formula I-B.
• each inhibitor at different times and by different routes, in some cases would be advantageous.
• the components in the combination i.e. the KRas G12C inhibitor compound of Formula (I), Formula I-A or Formula I-B, or a pharmaceutically acceptable salt thereof and the pan ErbB family inhibitor or a pharmaceutically acceptable salt thereof, need not be necessarily administered at essentially the same time or in any order.
• Oncology drugs are typically administered at the maximum tolerated dose (“MTD”), which is the highest dose of drug that does not cause unacceptable side effects.
• MTD maximum tolerated dose
• the pan ErbB family inhibitor or a pharmaceutically acceptable salt or a pharmaceutically composition thereof are each dosed at their respective MTDs.
• the KRas G12C inhibitor or a pharmaceutically acceptable salt or a pharmaceutically composition thereof is dosed at its MTD and the pan ErbB family inhibitor or a pharmaceutically acceptable salt or a pharmaceutically composition thereof is dosed in an amount less than its MTD.
• the KRas G12C inhibitor or a pharmaceutically acceptable salt or a pharmaceutically composition thereof is dosed at an amount less than its MTD and the pan ErbB family inhibitor or a pharmaceutically acceptable salt or a
• the KRas G12C inhibitor or a pharmaceutically acceptable salt or a pharmaceutically composition thereof and the pan ErbB family inhibitor or a pharmaceutically acceptable salt or a pharmaceutically composition thereof are each dosed at less than their respective MTDs.
• the administration can be so timed that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other.
• the KRas G12C inhibitor compound of Formula (I), Formula I-A or Formula I-B or a pharmaceutically acceptable salt or a pharmaceutically composition thereof is administered per day (i.e., in about 24 hour intervals) (i.e., QD).
• the KRas G12C inhibitor compound of Formula (I), Formula I-A or Formula I-B or a pharmaceutically acceptable salt or a pharmaceutically composition thereof is administered per day (i.e., TID).
• the pan ErbB family inhibitor or a pharmaceutically acceptable salt or a pharmaceutically composition thereof is administered QD. In another embodiment, the pan ErbB family inhibitor or a pharmaceutically acceptable salt or a pharmaceutically composition thereof is administered BID. In another embodiment, the pan ErbB family inhibitor or a pharmaceutically acceptable salt or a pharmaceutically composition thereof of the invention are administered TID.
• a single dose of KRas G12C inhibitor compound of Formula (I), Formula I-A or Formula I-B or a pharmaceutically acceptable salt or a pharmaceutically composition thereof and pan ErbB family inhibitor or a pharmaceutically acceptable salt or a pharmaceutically composition thereof are each administered once daily.
• the pan ErbB family inhibitor is an irreversible inhibitor.
• Exemplary irreversible pan ErbB family inhibitors for use in the methods herein include afatinib ((E)-N-(4- ((3-chloro-4-fluoiOphenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-4- (dimethylamino)but-2-enamide); dacomitinib ((2£)-/V- ⁇ 4-[(3-Chloro-4-fluoiOphenyl)amino]-7- methoxy-6-quinazolinyl ⁇ -4-(l-piperidinyl)-2-butenamide); canertinib (N-(4-((3-chloro-4- fluorophenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl)acrylamide); poziot
• the pan ErbB family inhibitor is a reversible inhibitor.
• Exemplary reversible pan EGFR family inhibitors include erlotinib ([6,7-Bis-(2-methoxy-ethoxy)- quinazolin-4-yl]-(3-ethynyl-phenyl)-amine)), gefitinib ((4-(3'-chloro-4'-fluoroanilino)-7- methoxy-6-(3-morpholinopropoxy)quinazoline), sapitinib (2-(4-((4-((3-chloro-2- fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-l-yl)-N-methylacetamide); varlitinib ((R)-N4-(3-chloro-4-(thiazol-2-ylmethoxy)phenyl)-N6-(4-methyl-
• the pan ErbB family inhibitor is an anti-EGFR antibody, an anti- F1ER2 antibody or a combination of an anti-EGFR antibody and anti-HER2 antibody, or pharmaceutical compositions thereof.
• the anti-EGFR antibody is necitumumab, panitumumab or cetuximab.
• the anti-EGFR antibody is cetuximab.
• the anti-HER2 antibodies suitable for use in the methods herein is pertuzumab, trastuzumab, or trastuzumab emtansine.
• the pan ErbB family inhibitor is a an EGFR inhibitor and a HER2 inhibitor, wherein the EGFR inhibitor and the HER2 inhibitor are independently selected from two agents selected from the group consisting of: AG 1478 FIC1 (/V-(3-Chlorophenyl)-6,7- dimethoxy-4-quinazolinanine hydrochloride); AG 494 (£)-2-Cyano-3 -(3 ,4-dihydro xyphenyl)- /V-phenyl-2-propenamide; AG 555 ( /f)-2-Cyano-3 -(3, 4-di hydroxypheny l)-/V-(3 -phenyl propyl)- 2-propenamide; AG 556 (is)-2-Cyano-3-(3,4-dihydroxyphenyl)-/V-(4-phenylbutyl)-2- propenamide; AG 825 (£ ' )-3-[3-[
• compositions thereof are provided.
• kits for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of a pan ErbB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutically composition thereof and a KRAS G12C inhibitor of Formula (I), Formula I-A or Formula I-B , or a pharmaceutically acceptable salt or a pharmaceutically composition thereof.
• the cancer is a KRas G12C-associated cancer.
• the KRas Gl2C-associated cancer is lung cancer.
• the invention provides for methods for increasing the sensitivity of a cancer cell to a KRas G 12C inhibitor, comprising contacting the cancer cell with an effective amount of a combination of a KRas G12C inhibitor compound of Formula (I), Formula I-A, or Formula I-B, or a pharmaceutically acceptable salt or a pharmaceutically composition thereof and a pan ErbB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the pan ErbB family inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12C inhibitor.
• the contacting is in vitro. In one embodiment, the contacting is in vivo.
• the combination therapy comprises a combination of a compound having the formula:
• pan ErbB family inhibitor is afatinib. In one embodiment, the pan ErbB family inhibitor is dacomitinib. In one embodiment, the pan ErbB family inhibitor is poziotinib. In one embodiment, the pan ErbB family inhibitor is erlotinib. In one embodiment, the pan ErbB family inhibitor is Gefitinib. In one embodiment, the pan ErbB family inhibitor is sapitinib. In one embodiment, the pan ErbB family inhibitor is tarloxotinib. In one
• the pan ErbB family inhibitor is an anti-EGFR antibody, wherein the anti-EGFR antibody is cetuximab.
• the combination therapy comprises a combination of a compound having the formula:
• pan ErbB family inhibitor is Afatinib. In one embodiment the pan ErbB family inhibitor is dacomitinib. in one embodiment, the pan ErbB family inhibitor is poziotinib. In one embodiment, the pan ErbB family inhibitor is erlotinib. In one embodiment, the pan ErbB family inhibitor is gefitinib. In one embodiment, the pan ErbB family inhibitor is sapitinib. In one embodiment, the pan ErbB family inhibitor is tarloxotinib. In one
• the pan ErbB family inhibitor is an anti-EGFR antibody, wherein the anti-EGFR antibody is cetuximab.
• the combination therapy comprises a combination of a compound having the formula:
• pan ErbB family inhibitor is afatinib. In one embodiment, the pan ErbB family inhibitor is dacomitinib. In one embodiment, the pan ErbB family inhibitor is poziotinib. In one embodiment, the pan ErbB family inhibitor is erlotinib. In one embodiment, the pan ErbB family inhibitor is Gefitinib. In one embodiment, the pan ErbB family inhibitor is sapitinib. In one embodiment, the pan ErbB family inhibitor is tarloxotinib. In one
• the pan ErbB family inhibitor is an anti-EGFR antibody, wherein the anti-EGFR antibody is cetuximab.
• the combination therapy comprises a combination of a compound having the formula:
• pan ErbB family inhibitor is afatinib. In one embodiment, the pan ErbB family inhibitor is Dacomitinib. In one embodiment, the pan ErbB family inhibitor is poziotinib. In one embodiment, the pan ErbB family inhibitor is erlotinib. In one embodiment, the pan ErbB family inhibitor is Gefitinib. In one embodiment, the pan ErbB family inhibitor is sapitinib. In one embodiment, the pan ErbB family inhibitor is tarloxotinib. In one
• the pan ErbB family inhibitor is an anti-EGFR antibody, wherein the anti-EGFR antibody is cetuximab.
• contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
• "contacting" a cancer cell includes the administration of a combination provided herein to an individual or subject, such as a human, having KRas G12C, as well as, for example, introducing a combination provided herein into a sample containing a cellular or purified preparation containing the KRas G12C.
• KRas G12C By negatively modulating the activity of KRas G12C, the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12C activity within the cell.
• the degree of covalent modification of KRas G12C may be monitored in vitro using well known methods, including those described in published international PCT
• the inhibitory activity of combination in cells may be monitored, for example, by measuring the inhibition of KRas G12C activity of the amount of phosphorylated ERK to assess the effectiveness of treatment and dosages may be adjusted accordingly by the attending medical practitioner.
• compositions and methods provided herein may be used for the treatment of a KRas G12C-associated cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a combination of a pan ErbB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutically composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula I-A, or Formula I-B, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the pan ErbB family inhibitor synergistically increases the sensitivity of the KRas Gl2C-associated cancer to the KRas G12C inhibitor.
• the KRas G12C-associated cancer is lung cancer.
• the therapeutically effective amount of the combination of a pan ErbB family inhibitor or a pharmaceutically acceptable salt or a pharmaceutically composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula I-A, or Formula I-B, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof results in an increased duration of overall survival (“OS”) in subjects relative to treatment with only the KRas G12C inhibitor.
• OS overall survival
• the therapeutically effective amount of the combination of a pan ErbB family inhibitor or a pharmaceutically acceptable salt or a pharmaceutically composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula I-A, or Formula I-B, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof results in an increased duration of progression-free survival (“PFS”) in subjects relative to treatment with only the KRas G12C inhibitor.
• PFS progression-free survival
• the therapeutically effective amount of the combination of a pan ErbB family inhibitor or a pharmaceutically acceptable salt or a pharmaceutically composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula I-A, or Formula I-B, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof results in increased tumor growth inhibition in subjects relative to treatment with only the KRas G12C inhibitor.
• the KRas G12C inhibitor is a compound selected from compound Nos. 1 -678 (as numbered in WO2019099524), or a pharmaceutically acceptable salt thereof (e.g., Example No. 234, 359, 478 or 507 or a pharmaceutically acceptable salt thereof).
• the pan ErbB family inhibitor is selected from afatinib, dacomitinib, poziotinib, erlotinib, gefitinib, sapitinib, and tarloxotinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and afatinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and dacomitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and poziotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and erlotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and gefitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and Tarloxotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and the anti-EGFR antibody cetuximab.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and afatinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and dacomitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and poziotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and erlotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and gefitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and tarloxotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and the anti-EGFR antibody cetuximab.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and afatinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and dacomitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and poziotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and erlotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and gefitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and tarloxotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and the anti-EGFR antibody cetuximab.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and afatinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and dacomitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and poziotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and erlotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and gefitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and tarloxotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and the anti-EGFR antibody cetuximab.
• the combination is useful for treating a KRas G12C-associated cancer.
• the KRas G12C-associated cancer is lung cancer.
• the pan ErbB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered in combination with the KRas G12C inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof once disease progression has been observed for KRas G12C monotherapy, in which the combination therapy results in enhanced clinical benefit or time of survival for the patient by increasing OS, PFS, tumor regression, tumor growth inhibition or the duration of stable disease in the patient.
• the KRas G12C inhibitor is a compound selected from compound Nos. 1-678 (as numbered in WO2019099524), or a pharmaceutically acceptable salt thereof (e.g., Example No. 234, 359, 478 or 507 or a pharmaceutically acceptable salt thereof).
• the pan ErbB family inhibitor is selected from afatinib, dacomitinib, poziotinib, erlotinib, gefitinib, sapitinib, and tarloxotinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and afatinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and dacomitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and poziotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and erlotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and gefitinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and tarloxotinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and the anti-EGFR antibody cetuximab.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and afatinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and dacomitinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and poziotinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and Erlotinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and gefitinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and tarloxotinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and the anti-EGFR antibody Cetuximab.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and afatinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and dacomitinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and poziotinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and erlotinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and tarloxotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and the anti-EGFR antibody cetuximab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and afatinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and dacomitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and poziotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and erlotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and tarloxotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and the anti-EGFR antibody cetuximab. In one embodiment of any of said combination therapies, the combination is useful for treating a KRas G12C-associated cancer.
• the KRas G12C-associated cancer is lung cancer.
• pan ErbB family inhibitor and the KRAS G12C inhibitor are administered on the same day.
• pan ErbB family inhibitor and the KRAS G12C inhibitor are administered on different days.
• compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
• tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
• these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinom
• kidney adenocarcinoma, Wilm's tumor
• liver nephroblastoma
• lymphoma lymphoma
• leukemia bladder and urethra
• squamous cell carcinoma transitional cell carcinoma, adenocarcinoma
• prostate adenocarcinoma, sarcoma
• testis seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma
• Liver Liver:
• hepatoma hepatocellular carcinoma
• cholangiocarcinoma hepatoblastoma
• angiosarcoma hepatocellular adenoma
• Biliary tract gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma
• Bone osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma,
• osteochronfroma osteocartilaginous exostoses
• benign chondroma chondroblastoma
• chondromyxofibroma osteoid osteoma
• giant cell tumors Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma,
• meningiosarcoma meningiosarcoma, gliomatosis
• brain astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma,
• retinoblastoma congenital tumors
• spinal cord neurofibroma meningioma
• glioma sarcoma
• Gynecological uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous
• cystadenocarcinoma unclassified carcinoma
• granulosa-thecal cell tumors Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin:
• malignant melanoma basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands:
• the cancer is non-small cell lung cancer.
• Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising (a) determining that cancer is associated with a KRas G12C mutation (e.g., a KRas G12C-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a combination of a pan ErbB family inhibitor and a KRas G12C inhibitor compound of Formula I, Formula I-A, Formula 1-B, or pharmaceutically acceptable salts or
• a KRas G12C mutation e.g., a KRas G12C-associated cancer
• a regulatory agency-approved e.g., FDA-approved, assay or kit
• the pan ErbB inhibitor synergistically increases the sensitivity of the KRas G12C-associated cancer to the KRas G12C inhibitor.
• the KRas G12C inhibitor is a compound selected from compound Nos. 1-678 (as numbered in WO2019099524), or a pharmaceutically acceptable salt thereof (e.g., Example No. 234, 359, 478 or 507 or a pharmaceutically acceptable salt thereof).
• the pan ErbB family inhibitor is selected from afatinib, dacomitinib, poziotinib, Erlotinib, gefitinib, sapitinib, and tarloxotinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and afatinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and dacomitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and poziotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and erlotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and gefitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and tarloxotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and the anti-EGFR antibody cetuximab.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and afatinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and dacomitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and poziotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and erlotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and gefitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and tarloxotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and the anti-EGFR antibody cetuximab.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and afatinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and dacomitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and poziotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and erlotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and gefitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and tarloxotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and the anti-EGFR antibody cetuximab.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and afatinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and dacomitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and poziotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and erlotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and gefitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and tarloxotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and the anti-EGFR antibody cetuximab. In one embodiment of any of said combination therapies, the combination is useful for treating a KRas G12C-associated cancer. In one embodiment, the KRas Gl2C-associated cancer is lung cancer.
• the pan ErbB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered in combination with the KRas G12C inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof once disease progression has been observed for KRas G12C monotherapy, in which the combination therapy results in enhanced clinical benefit or time of survival for the patient by increasing OS, PFS, tumor regression, tumor growth inhibition or the duration of stable disease in the patient.
• the KRas G12C inhibitor is a compound selected from compound Nos. 1-678 (as numbered in WO2019099524), or a pharmaceutically acceptable salt thereof (e.g., Example No. 234, 359, 478 or 507 or a pharmaceutically acceptable salt thereof).
• the pan ErbB family inhibitor is selected from Afatinib, dacomitinib, poziotinib, erlotinib, gefitinib, sapitinib, and tarloxotinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and afatinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and dacomitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and poziotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and erlotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and gefitinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and tarloxotinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and the anti-EGFR antibody cetuximab.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and afatinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and dacomitinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and poziotinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and erlotinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and gefitinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and tarloxotinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and the anti-EGFR antibody cetuximab.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and afatinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and dacomitinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and poziotinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and erlotinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and tarloxotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and the anti-EGFR antibody cetuximab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and afatinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and dacomitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and poziotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and erlotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and tarloxotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and the anti-EGFR antibody cetuximab. In one embodiment of any of said combination therapies, the combination is useful for treating a KRas G12C-associated cancer.
• the KRas Gl2C-associated cancer is lung cancer.
• a compound of Formula I, or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered as a capsule during the period of time.
• a tablet or capsule formulation of a compound of Formula I comprises about 10 mg to about 100 mg (e.g., about 10 mg to about 95 mg, about 10 mg to about 90 mg, about 10 mg to about 85 mg, about 10 mg to about 80 mg, about 10 mg to about 75 mg, about 10 mg to about 70 mg, about 10 mg to about 65 mg, about 10 mg to about 60 mg, about 10 mg to about 55 mg, about 10 mg to about 50 mg, about 10 mg to about 45 g, about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 10 mg to about 25 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 15 mg to about 100 mg, about 15 mg to about 95 mg, about 15 mg to about 90 mg, about 15 mg to about 85 mg, about 15 mg to about 80 mg, about 15 mg to about 75 mg,
• a compound of Formula I is orally administered once a day (QD) on a daily basis during a period of time. In one embodiment, a compound of Formula I is orally administered twice a day (BID) on a daily basis during a period of time.
• a compound of Formula I is orally administered in the amount of about 20 mg to about 500 mg (e.g., about 20 mg to about 480 mg, about 20 mg to about 460 mg, about 20 mg to about 440 mg, about 20 mg to about 420 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 g, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 500 mg, about 40 mg to about 480 mg, about 40 mg to about 460 mg, about 40 mg to about
• the combination therapy comprises oral administration of a compound of Formula I once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg (e.g., about 10 mg to about 380 mg, about 10 mg to about 360 mg, about 10 mg to about 340 mg, about 10 mg to about 320 mg, about 10 mg to about 300 mg, about 10 mg to about 280 mg, about 10 mg to about 260 mg, about 10 mg to about 240 mg, about 10 mg to about 220 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 140 mg, about 10 mg to about 120 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 10 mg to about 40 mg, about 10 mg to about 20 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about
• the KRAS G12C inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof is orally administered once daily. In one embodiment, the KRAS G12C inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is orally administered twice daily.
• pan ErbB family inhibitor synergistically increases the activity of KRas G12C inhibitor compound of Formula (I), Formula I-A or Formula I-B against cancer cell lines expressing KRas G12C. Any method for determining whether two compounds exhibit synergy may be used for determining the synergistic effect of the combination.
• the mathematical models use data obtained from single agent values to determine the predicted additive effect of the combination which is compared to the observed effect for the combination. If the observed effect is greater than the predicted effect, the combination is deemed to be synergistic.
• the Bliss independence model compares the observed combination response (Yo) with the predicted combination response (Yp), which was obtained based on the assumption that there is no effect from drug-drug interactions.
• the combination effect is declared synergistic if Yo is greater than Yp.
• “synergistic effect” as used herein refers to combination of a KRAS inhibitor or a pharmaceutically acceptable salt thereof, and a pan ErbB family inhibitor or a pharmaceutically acceptable salt thereof producing an effect, for example, any of the beneficial or desired results including clinical results or endpoints as described herein, which is greater than the sum of the effect observed when a compound of Formula I, Formula I-A or Formula I-B or a pharmaceutically acceptable salt thereof (e.g., 1-678 (as numbered in
• the KRas G12C inhibitor is a compound selected from compound Nos. 1-678 (as numbered in
• the pan ErbB family inhibitor is selected from afatinib, dacomitinib, gefitinib, sapitinib, tarloxotinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and afatinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and dacomitinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and gefitinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and the anti- EGFR antibody cetuximab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and afatinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and dacomitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and gefitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and tarloxotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and the anti-EGFR antibody cetuximab.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and afatinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and dacomitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and gefitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and tarloxotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and the anti-EGFR antibody cetuximab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and afatinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and dacomitinib.
• the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and gefitinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and tarloxotinib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and the anti- EGFR antibody cetuximab. In one embodiment of any of said combination therapies, the combination is useful for treating a KRas G12C-associated cancer. In one embodiment, the KRas Gl2C-associated cancer is lung cancer.
• the methods provided herein can result in a 1% to 99% (e.g., 1% to 98%, 1% to 95%, 1% to 90%, 1 to 85%, 1 to 80%, 1% to 75%, 1% to 70%, 1% to 65%, 1% to 60%, 1% to 55%, 1% to 50%, 1 % to 45%, 1% to 40%, 1% to 35%, 1% to 30%, 1% to 25%, 1% to 20%, 1 % to 15%, 1% to 10%, 1 % to 5%, 2% to 99%, 2% to 90%, 2% to 85%, 2% to 80%, 2% to 75%, 2% to 70%, 2% to 65%, 2% to 60%, 2% to 55%, 2% to 50%, 2% to 45%, 2% to 40%, 2% to 35%, 2% to 30%, 2% to 25%, 2% to 20%, 2% to 15%, 2% to 10%, 2% to 5%, 4% to 99%, 4% to 98%, 1% to 95%,
• 2 weeks and 7 months between 2 weeks and 6 months, between 2 weeks and 5 months, between 2 weeks and 4 months, between 2 weeks and 3 months, between 2 weeks and 2 months, between 2 weeks and 1 month, between 1 month and 2 years, between 1 month and 22 months, between 1 month and 20 months, between 1 month and 18 months, between 1 month and 16 months, between 1 month and 14 months, between 1 month and 12 months, between 1 month and 10 months, between 1 month and 9 months, between 1 month and 8 months, between 1 month and 7 months, between 1 month and 6 months, between 1 month and 6 months, between 1 month and 5 months, between 1 month and 4 months, between 1 month and
• 3 months between 1 month and 2 months, between 2 months and 2 years, between 2 months and 22 months, between 2 months and 20 months, between 2 months and 18 months, between 2 months and 16 months, between 2 months and 14 months, between 2 months and 12 months, between 2 months and 10 months, between 2 months and 9 months, between 2 months and 8 months, between 2 months and 7 months, between 2 months and 6 months, or between 2 months and 5 months, between 2 months and 4 months, between 3 months and 2 years, between 3 months and 22 months, between 3 months and 20 months, between 3 months and 18 months, between 3 months and 16 months, between 3 months and 14 months, between 3 months and 12 months, between 3 months and 10 months, between 3 months and 8 months, between 3 months and 6 months, between 4 months and 2 years, between 4 months and 22 months, between 4 months and 20 months, between 4 months and 18 months, between 4 months and 16 months, between 3 months and 14 months, between 3 months and 12 months, between 3 months and 10 months, between 3 months and 8 months, between 3 months and 6 months, between 4 months and 2 years
• the patient before treatment with the compositions or methods of the invention, was treated with one or more of a chemotherapy, a targeted anticancer agent, radiation therapy, and surgery, and optionally, the prior treatment was unsuccessful; and/or the patient has been administered surgery and optionally, the surgery was unsuccessful; and/or the patient has been treated with a platinum- based chemotherapeutic agent, and optionally, the patient has been previously determined to be non-responsive to treatment with the platinum-based chemotherapeutic agent; and/or the patient has been treated with a kinase inhibitor, and optionally, the prior treatment with the kinase inhibitor was unsuccessful; and/or the patient was treated with one or more other therapeutic agent(s).
• the present invention also relates to a kit comprising a pan ErbB family inhibitor, or a pharmaceutically acceptable salt thereof and a KRas G12C inhibitor compound of Formula (I), Formula I-A or Formula I-B or a pharmaceutically acceptable salt thereof. Also provided is a kit comprising a pan ErbB family inhibitor or a pharmaceutically acceptable salt thereof and a KRas G12C inhibitor compound of Formula (I), Formula I-A or Formula I-B or a
• the invention provides a kit containing a dose of a pan ErbB family inhibitor and dose of a KRas G12C inhibitor compound of Formula (I), Formula I-A or Formula I-B or a pharmaceutically acceptable salt thereof in an amount effective to inhibit proliferation of cancer cells, particularly KRas G12C-expressing cancer cells, in a subject.
• the kit in some cases includes an insert with instructions for administration of the pan ErbB family inhibitor and a KRas G12C inhibitor compound of Formula (I), Formula I-A or Formula I-B.
• the insert may provide a user with one set of instructions for using a pan ErbB family inhibitor in combination with a KRas G12C inhibitor compound of Formula (I), Formula I-A or Formula 1- B.
• This Example illustrates that the combination of exemplary KRas G12C inhibitor compounds of Formula I, Formula I-A and Formula 1-B or a pharmaceutically acceptable salt thereof (e.g., a compound selected from compound Example Nos 1-678, or a pharmaceutically acceptable salt thereof, e.g., Example No. 234, 359, 478 or 507, or a pharmaceutically acceptable salt thereof) and a pan ErbB family inhibitor or a pharmaceutically acceptable salt or a pharmaceutical composition thereof synergistically inhibits the growth of tumor cell lines that express KRas G12C.
• a pharmaceutically acceptable salt thereof e.g., a compound selected from compound Example Nos 1-678, or a pharmaceutically acceptable salt thereof, e.g., Example No. 234, 359, 478 or 507, or a pharmaceutically acceptable salt thereof
• a pan ErbB family inhibitor or a pharmaceutically acceptable salt or a pharmaceutical composition thereof synergistically inhibits the growth of tumor cell lines that express KRas G12C.
• a panel of 9 lung cancer and 1 colorectal cell lines harboring KRas G12C mutations was assembled to determine whether combining pan ErbB family inhibitors with exemplary KRas G12C inhibitors disclosed herein results in synergistic activity.
• NCI- H1373 ATCC CRL-5866
• NCI-H1792 ATCC CRL-5895
• NCI-H2030 ATCC CRL-5985
• NCI-H2122 ATCC CRL-5985
• PICC1 171 KCLB 71 171
• HCC44 DSMZ ACC-534
• LU99 RBC 1900
• SW1573 ATCC CRL-2170
• SW837 ATCC CCL-235
• KYSE-410 ECACC 94072023
• Assays for determining the synergy score for the pairwise combinations for each cell line were performed in triplicate. Three 96-well plates plus an additional 4 wells of a separate 96- well control plate for determining baseline luminescence were seeded with 2000 cells/well of a particular cell line in a total volume of 90m1 of a suitable growth medium for that cell line, e.g., RPMI 1640 medium supplemented with 10% FBS and any cell line specific reagents need for growth. The plates were incubated overnight at 37°C in a 5% CO2 atmosphere.
• a suitable growth medium for that cell line e.g., RPMI 1640 medium supplemented with 10% FBS and any cell line specific reagents need for growth.
• a series of working stock 1000X drug dilutions in 100% DMSO was prepared that includes an 8 point single agent dilution of the exemplary KRas G12C inhibitor of Formula (1) and a 5-point single agent dilution of the pan ErbB family inhibitor.
• the dilutions used for the KRas G12C inhibitor and the pan ErbB family inhibitor varied for each individual compound but were in the range of 3- to 6-fold/serial dilution.
• Example Number refers to the example number for each compound as disclosed in published International PCT application WO2019099524.
• a 10X intermediate dosing plate was prepared in serum free RPMI medium that contains arrayed single agent dilutions of exemplary KRas G12C inhibitor of Formula (I) or the Pan ErbB inhibitor.
• a matrix of 40 dilution combinations of exemplary KRas G12C inhibitor of Formula (I), Formula I-A or Formula I-B and the pan ErbB family inhibitor was prepared as test samples.
• a composite score of greater than or equal to 27 was interpreted as a synergistic hit whereas a composite score between 17 and 26 indicates potential synergy.
• mice were inoculated in the right hind flank with cells or patient derived tumor samples harboring a KRas G12C mutation. When tumor volumes reached between 200 - 400 mm 3 in size, the mice were divided into four groups of 5-12 mice each. The first group was administered vehicle only. The second group was administered a single agent dose of the KRas G12C inhibitor at a concentration that yields a maximal biological effect or a less than maximal biological effect, depending on the cell line and the single agent activity, that does not result in complete tumor regression.
• the third group was administered a single agent dose of the pan ErbB inhibitor at a concentration that yields a maximal biological effect or a less than maximal biological effect, depending on the cell line and the single agent activity, that also does not result in complete tumor regression.
• the fourth group was administered the single agent dose of the KRas G12C inhibitor in combination with the single agent dose of the pan ErbB family inhibitor.
• the treatment period varied from cell line to cell line but typically was between 21-35 days. Tumor volumes were measured using a caliper every two - three days and tumor volumes were calculated by the formula: 0.5 x (Length x Width) 2 .
• a greater degree of tumor regression for the combination in this model demonstrates that the combination therapy is likely to have a clinically meaningful benefit to treated subjects relative to treatment with only a KRas G12C inhibitor.
• Ill tumor volume reached -300 mm 3 (Day 1 1) 5 mice in each of the four groups were administered p.o. daily for 21 days: vehicle only (10% Captisol), 100 mg/kg of the KRas G12C inhibitor Compound 478 (10% Captisol in 50 mM citrate buffer, pH 5.0), 12.5 mg/kg of the pan ErbB family inhibitor Afatinib (0.5% methylcellulose/0.4% Tween-80), or 100 mg/kg of the KRas G12C inhibitor Compound 478 and 12.5 mg/kg of Afatinib.
• Tumor volumes were measured at pre-specified days set forth below. Tumor volumes for the five mice per group were averaged and are reported in Table 4a (H2122 cell line), 4b (KYSE-410 cell line) and 4c (LU6405 cells).
• mice were administered every third day 0.25 mg/kg i.p of the pan ErbB family inhibitor antibody Cetuximab (PBS, pH 7.2), or 100 mg/kg of KRas G12C inhibitor Compound 478 p.o and 0.25 mg/kg of Cetuximab i.p every three days. Tumor volumes were measured at pre- specified days set forth below. Tumor volumes for the five mice per group were averaged and are reported in Table 5a (CR6256 cell line) and 5b (CR2528 cell line).
• tarloxotinib 10 mg/kg Beta- cyclodextrin
• KRas G12C inhibitor Compound 478 p.o and 48 mg/kg of tarloxotinib i.p every seven days.
• Tumor volumes were measured at pre-specified days set forth below. Tumor volumes for the five mice per group were averaged and are reported in Table 6a (KYSE-410 cell line) and 6b (H2122 cell line).

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